Gonzalez Kelly D, Hill Kathleen A, Li Kai, Li Wenyan, Scaringe William A, Wang Ji-Cheng, Gu Dongqing, Sommer Steve S
Department of Molecular Genetics, City of Hope National Medical Center, Duarte, California.
Hum Mutat. 2007 Jan;28(1):69-80. doi: 10.1002/humu.20416.
Microindels, defined as mutations that result in a colocalized microinsertion and microdeletion with a net gain or loss of between 1 and 50 nucleotides, may be an important contributor to cancer. We report the first comprehensive analysis of somatic microindels. Our large database of mutations in the lacI transgene of Big Blue((R)) mice contains 0.5% microindels, 2.8% pure microinsertions, and 11.5% pure microdeletions. There appears to be no age, gender, or tissue-type specificity in the frequency of microindels. Of the independent somatic mutations that result in a net in-frame insertion or deletion, microindels are responsible for 13% of protein expansions and 6% of protein contractions. These in-frame microindels may play a crucial role in oncogenesis and evolution via "protein tinkering" (i.e., modest expansion or contraction of proteins). Four characteristics suggest that microindels are caused by unique mechanisms, not just simple combinations of the same mechanisms that cause pure microinsertions and pure microdeletions. First, microinsertions and microdeletions commonly occur at hotspots, but none of the 30 microindels are recurrent. Second, the sizes of the deletions and insertions in microindels are larger and more varied than in pure microdeletions and pure microinsertions. Third, microinsertions overwhelmingly repeat the adjacent base (97%) while the insertions in microindels do so only infrequently (17%). Fourth, analysis of the sequence contexts of microindels is consistent with unique mechanisms including recruitment of translesion DNA synthesis polymerases. The mouse somatic microindels have characteristics similar to those of human germline microindels, consistent with similar causative mechanisms in mouse and human, and in soma and germline.
微插入缺失（定义为导致共定位的微插入和微缺失且净增减1至50个核苷酸的突变）可能是癌症的一个重要促成因素。我们报告了对体细胞微插入缺失的首次全面分析。我们在大蓝（R）小鼠的lacI转基因中的大型突变数据库包含0.5%的微插入缺失、2.8%的纯微插入和11.5%的纯微缺失。微插入缺失的频率似乎没有年龄、性别或组织类型特异性。在导致净读框内插入或缺失的独立体细胞突变中，微插入缺失占蛋白质扩增的13%和蛋白质收缩的6%。这些读框内微插入缺失可能通过“蛋白质修补”（即蛋白质的适度扩增或收缩）在肿瘤发生和进化中起关键作用。四个特征表明微插入缺失是由独特机制引起的，而不仅仅是导致纯微插入和纯微缺失的相同机制的简单组合。首先，微插入和微缺失通常发生在热点区域，但30个微插入缺失中没有一个是复发的。其次，微插入缺失中的缺失和插入大小比纯微缺失和纯微插入更大且更多样化。第三，微插入绝大多数重复相邻碱基（97%），而微插入缺失中的插入很少这样做（17%）。第四，对微插入缺失的序列背景分析与包括跨损伤DNA合成聚合酶募集在内的独特机制一致。小鼠体细胞微插入缺失具有与人类种系微插入缺失相似的特征，这与小鼠和人类以及体细胞和种系中相似的致病机制一致。
